TY - JOUR
T1 - Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia
AU - Xu, Lian
AU - Hunter, Zachary R.
AU - Tsakmaklis, Nicholas
AU - Cao, Yang
AU - Yang, Guang
AU - Chen, Jie
AU - Liu, Xia
AU - Kanan, Sandra
AU - Castillo, Jorge J.
AU - Tai, Yu Tzu
AU - Zehnder, James L.
AU - Brown, Jennifer R.
AU - Carrasco, Ruben D.
AU - Advani, Ranjana
AU - Sabile, Jean M.
AU - Argyropoulos, Kimon
AU - Lia Palomba, M.
AU - Morra, Enrica
AU - Trojani, Alessandra
AU - Greco, Antonino
AU - Tedeschi, Alessandra
AU - Varettoni, Marzia
AU - Arcaini, Luca
AU - Munshi, Nikhil M.
AU - Anderson, Kenneth C.
AU - Treon, Steven P.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - CXCR4WHIM somatic mutations are distinctive to Waldenström Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4WHIM mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction (AS-PCR) assays for detecting the most common CXCR4WHIM mutations (CXCR4S338X C>A and C>G) in WM. The AS-PCR assays detected CXCR4S338X mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4WHIM mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4S338X mutations were primarily subclonal, with highly variable clonal distribution (median 35·1%, range 1·2-97·5%). Combined AS-PCR and Sanger sequencing revealed multiple CXCR4WHIM mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show that CXCR4WHIM mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88L265P in WM oncogenesis. The presence of multiple CXCR4WHIM mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.
AB - CXCR4WHIM somatic mutations are distinctive to Waldenström Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4WHIM mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction (AS-PCR) assays for detecting the most common CXCR4WHIM mutations (CXCR4S338X C>A and C>G) in WM. The AS-PCR assays detected CXCR4S338X mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4WHIM mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4S338X mutations were primarily subclonal, with highly variable clonal distribution (median 35·1%, range 1·2-97·5%). Combined AS-PCR and Sanger sequencing revealed multiple CXCR4WHIM mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show that CXCR4WHIM mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88L265P in WM oncogenesis. The presence of multiple CXCR4WHIM mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.
KW - WHIM
KW - CXCR4
KW - IgM MGUS
KW - Marginal Zone Lymphoma
KW - MYD88 L265P
KW - Waldenström macroglobulinaemia
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U2 - 10.1111/bjh.13897
DO - 10.1111/bjh.13897
M3 - Article
AN - SCOPUS:84958947359
VL - 172
SP - 735
EP - 744
JO - British Journal of Haematology
JF - British Journal of Haematology
SN - 0007-1048
IS - 5
ER -